CYP7B1: one cytochrome P450, two human genetic diseases, and multiple physiological functions

Abstract

The CYP7B1 cytochrome P450 enzyme hydroxylates carbons 6 and 7 of the B ring of oxysterols and steroids. Hydroxylation reduces the biological activity of these substrates and facilitates their conversion to end products that are readily excreted from the body. CYP7B1 is expressed in the liver, reproductive tract, and brain and performs different physiological functions in each tissue. Hepatic CYP7B1 activity is crucial for the inactivation of oxysterols and their subsequent conversion into bile salts. Loss of CYP7B1 activity is associated with liver failure in children. In the reproductive tract, the enzyme metabolizes androgens that antagonize estrogen action; mice without CYP7B1 have abnormal prostates and ovaries. The role of CYP7B1 in brain is under investigation; recent studies show that spastic paraplegia type 5, a progressive neuropathy, is caused by loss-of-function mutations in the human gene.

FIGURE 1.

CYP7B1 and reactions catalyzed. A, schematic of the 506-amino acid enzyme showing regions encoded by the six exons of the gene and the positions marked by arrows at which five introns interrupt individual codons. The heme cofactor is covalently bound to Cys⁴⁴⁹. B, 7α-hydroxylation of substrates (1, pregnenolone; 2, dehydroepiandrosterone; 3, 25-hydroxycholesterol; 4, 27-hydroxycholesterol) and 6α-hydroxylation of 5α-androstane-3β,17β-diol. POR, cytochrome P450 oxidoreductase.

FIGURE 2.

Mutations in human CYP7B1 gene. Exons are indicated by shaded boxes drawn to scale. Introns are indicated by dashed lines and are not drawn to scale. Transcript coding regions are shaded blue; 5′- and 3′-untranslated regions are white. Mutations in subjects with liver failure are shown above the gene; those found in spastic paraplegia type 5 are shown below the gene.